Abstract: P619
Type: Poster Sessions
Abstract Category: Therapy - Tools for detecting therapeutic response
Background: It is critically important, for independent daily living, to preserve upper limb function in patients with primary progressive multiple sclerosis (PPMS), especially among those with advanced disability. In the Phase III ORATORIO study (NCT01194570), ocrelizumab (OCR) demonstrated efficacy vs placebo (PBO) in reducing upper limb dysfunction, assessed by 9-Hole Peg Test (9HPT) in PPMS patients with Expanded Disability Status Scale (EDSS) ≤6.5. An important unmet need would be addressed if OCR benefited upper limb function in more disabled PPMS patients ineligible for inclusion in ORATORIO who are more representative of real-world clinical settings.
Objective: To assess the effect of OCR on upper limb function in subgroups of more disabled/older patients in ORATORIO, and thereby to inform the design of ORATORIO-HAND, a Phase IIIb, randomised, double-blind, placebo-controlled study in PPMS.
Methods: In ORATORIO, PPMS patients (N=732) with EDSS 3.0-6.5, aged 18-55 years were randomised (2:1) to OCR or PBO for ≥120 weeks and until a pre-specified number of EDSS progression events (primary endpoint) occurred. Efficacy of OCR in preventing confirmed 20% worsening in 9HPT was investigated in pre-specified baseline (BL) subgroups of EDSS ≥6.0 and age >45 years, and in an additional subgroup with 9HPT times >25 seconds (s).
Results: Subgroup analyses indicate that OCR reduces progression of upper limb disability in more disabled/older PPMS patients: relative risk reduction with OCR vs PBO in 12-week confirmed 9HPT was similar in patients with BL EDSS < 6.0 and ≥6.0 (40% vs 38%, interaction p=0.9187). It was also similar in patients with BL 9HPT ≤25s and >25s (49% vs 44%, interaction p=0.8221); however, 9HPT progression events mainly occurred in patients with 9HPT >25s vs ≤25s (PBO: 34.3% vs 17.8%; OCR: 21.5% vs 9.9%). In patients ≤45 years, OCR showed a weak trend for greater risk reduction for 9HPT progression than those >45 years (52% vs 33%, interaction p=0.2854).
Conclusions: Based in part on the observed encouraging treatment effect of OCR on upper limb function, the ORATORIO-HAND study has been designed to further investigate the efficacy of OCR on upper limb function in a rigorous, controlled manner. Eligible patients will be randomised (1:1) to OCR or PBO for ≥120 weeks and until a pre-specified number of confirmed 9HPT progression events (primary endpoint) occur. Key entry criteria include EDSS 3.0-8.0, age 18-65 years, 9HPT >25s. Screening will begin Q4 2018.
Disclosure: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK.
G. Giovannoni has received honoraria from AbbVie, Atara Biotherapeutics, Bayer HealthCare, Biogen, Canbex Therapeutics, F. Hoffmann-La Roche Ltd, Five Prime Therapeutics, Genzyme, GlaxoSmithKline, GW Pharmaceuticals, Merck, Merck Serono, Novartis, Protein Discovery Laboratories, Synthon, Teva, UCB and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz and Novartis; and compensation from Elsevier.
L. Airas has received honoraria from Biogen, F. Hoffmann-La Roche Ltd, Genzyme, Merck Serono and Teva, and institutional research grant support from Biogen, Genzyme, Merck Serono and Novartis.
R. Bove has received research support from the National Multiple Sclerosis Society, Hilton Foundation, California Initiative to Advance Precision Medicine, Doris Duke Award, Sherak Foundation and Akili Interactive; and has received personal compensation for medical legal consulting and for consulting or serving on the advisory boards of F. Hoffmann-La Roche Ltd, Sanofi Genzyme and Novartis.
A. Boyko has been working as an advisory board member and as a speaker, and has participated in clinical trials sponsored by Teva, Biogen, Roche, Sanofi Genzyme, Merck, BIOCAD and Generium.
G. Cutter has served on data and safety monitoring boards for AMO Pharmaceuticals, Biolinerx, Horizon Pharmaceuticals, Merck, Merck/Pfizer, Opko Biologics, Neurim, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva pharmaceuticals, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee); and has served on consulting or advisory boards for Atara Biotherapeutics, Axon, Biogen, Biotherapeutics, Argenix, Brainstorm Cell Therapeutics, Charleston Labs Inc, Click Therapeutics, Genzyme, Genentech, GW Pharma, Klein-Buendel Inc., Medimmune, Medday, Novartis, Roche, Scifluor, Somahlution, Teva pharmaceuticals, TG Therapeutics, and UT Houston. Dr. Cutter is employed by the University of Alabama at Birmingham and is president of Pythagoras, Inc., a private consulting company located in Birmingham, AL, USA.
J. Hobart has received consulting fees, honoraria and support to attend meetings or research support from Acorda, Asubio, Bayer Schering, Biogen Idec, F. Hoffmann-La Roche Ltd, Genzyme, Merck Serono, Novartis, Oxford PharmaGenesis, Oxford Health Policy Forum and Teva.
J. Kuhle has received speaker fees, research support, travel support and/or served on advisory boards for ECTRIMS, Swiss MS Society, Swiss National Research Foundation (320030_160221), University of Basel, Bayer, Biogen, F. Hoffmann-La Roche Ltd, Genzyme, Merck, Novartis, Protagen AG and Teva.
J. Oh has received research grant funding from the MS Society of Canada, National MS Society, Brain Canada, Biogen-Idec, and Sanofi-Genzyme; and has received personal compensation for consulting or speaking from EMD-Serono, Sanofi-Genzyme, Biogen-Idec, Novartis, and Roche.
C. Tur acknowledges 2015 postdoctoral research ECTRIMS Fellowships, and has also received honoraria and support from Biogen, Bayer, F. Hoffmann-La Roche Ltd, Ismar Healthcare, Merck Serono, Novartis, Sanofi and Teva.
M. Garas is an employee and shareholder of F. Hoffmann-La Roche Ltd.
F. Model is an employee and shareholder of F. Hoffmann-La Roche Ltd.
M. Manfrini is an employee and shareholder of F. Hoffmann-La Roche Ltd.
J. Wolinsky has served on advisory boards, data monitoring or steering committees and has consulting agreements from the following entities: AbbVie, Actelion, Alkermes, Bayer HealthCare, Biogen, Bionest, Celgene, Clene Nanomedicine, EMD Serono, Forward Pharma A/S, GeNeuro, MedDay Pharmaceuticals, Novartis Pharmaceuticals, Otsuka, PTC Therapeutics, Roche Genentech, Sanofi Genzyme, Strategic Consultants International, Takeda and Teva Pharmaceuticals; royalties are received for outlicensed monoclonal antibodies through UTHealth from Millipore Corporation.
Abstract: P619
Type: Poster Sessions
Abstract Category: Therapy - Tools for detecting therapeutic response
Background: It is critically important, for independent daily living, to preserve upper limb function in patients with primary progressive multiple sclerosis (PPMS), especially among those with advanced disability. In the Phase III ORATORIO study (NCT01194570), ocrelizumab (OCR) demonstrated efficacy vs placebo (PBO) in reducing upper limb dysfunction, assessed by 9-Hole Peg Test (9HPT) in PPMS patients with Expanded Disability Status Scale (EDSS) ≤6.5. An important unmet need would be addressed if OCR benefited upper limb function in more disabled PPMS patients ineligible for inclusion in ORATORIO who are more representative of real-world clinical settings.
Objective: To assess the effect of OCR on upper limb function in subgroups of more disabled/older patients in ORATORIO, and thereby to inform the design of ORATORIO-HAND, a Phase IIIb, randomised, double-blind, placebo-controlled study in PPMS.
Methods: In ORATORIO, PPMS patients (N=732) with EDSS 3.0-6.5, aged 18-55 years were randomised (2:1) to OCR or PBO for ≥120 weeks and until a pre-specified number of EDSS progression events (primary endpoint) occurred. Efficacy of OCR in preventing confirmed 20% worsening in 9HPT was investigated in pre-specified baseline (BL) subgroups of EDSS ≥6.0 and age >45 years, and in an additional subgroup with 9HPT times >25 seconds (s).
Results: Subgroup analyses indicate that OCR reduces progression of upper limb disability in more disabled/older PPMS patients: relative risk reduction with OCR vs PBO in 12-week confirmed 9HPT was similar in patients with BL EDSS < 6.0 and ≥6.0 (40% vs 38%, interaction p=0.9187). It was also similar in patients with BL 9HPT ≤25s and >25s (49% vs 44%, interaction p=0.8221); however, 9HPT progression events mainly occurred in patients with 9HPT >25s vs ≤25s (PBO: 34.3% vs 17.8%; OCR: 21.5% vs 9.9%). In patients ≤45 years, OCR showed a weak trend for greater risk reduction for 9HPT progression than those >45 years (52% vs 33%, interaction p=0.2854).
Conclusions: Based in part on the observed encouraging treatment effect of OCR on upper limb function, the ORATORIO-HAND study has been designed to further investigate the efficacy of OCR on upper limb function in a rigorous, controlled manner. Eligible patients will be randomised (1:1) to OCR or PBO for ≥120 weeks and until a pre-specified number of confirmed 9HPT progression events (primary endpoint) occur. Key entry criteria include EDSS 3.0-8.0, age 18-65 years, 9HPT >25s. Screening will begin Q4 2018.
Disclosure: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK.
G. Giovannoni has received honoraria from AbbVie, Atara Biotherapeutics, Bayer HealthCare, Biogen, Canbex Therapeutics, F. Hoffmann-La Roche Ltd, Five Prime Therapeutics, Genzyme, GlaxoSmithKline, GW Pharmaceuticals, Merck, Merck Serono, Novartis, Protein Discovery Laboratories, Synthon, Teva, UCB and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz and Novartis; and compensation from Elsevier.
L. Airas has received honoraria from Biogen, F. Hoffmann-La Roche Ltd, Genzyme, Merck Serono and Teva, and institutional research grant support from Biogen, Genzyme, Merck Serono and Novartis.
R. Bove has received research support from the National Multiple Sclerosis Society, Hilton Foundation, California Initiative to Advance Precision Medicine, Doris Duke Award, Sherak Foundation and Akili Interactive; and has received personal compensation for medical legal consulting and for consulting or serving on the advisory boards of F. Hoffmann-La Roche Ltd, Sanofi Genzyme and Novartis.
A. Boyko has been working as an advisory board member and as a speaker, and has participated in clinical trials sponsored by Teva, Biogen, Roche, Sanofi Genzyme, Merck, BIOCAD and Generium.
G. Cutter has served on data and safety monitoring boards for AMO Pharmaceuticals, Biolinerx, Horizon Pharmaceuticals, Merck, Merck/Pfizer, Opko Biologics, Neurim, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva pharmaceuticals, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee); and has served on consulting or advisory boards for Atara Biotherapeutics, Axon, Biogen, Biotherapeutics, Argenix, Brainstorm Cell Therapeutics, Charleston Labs Inc, Click Therapeutics, Genzyme, Genentech, GW Pharma, Klein-Buendel Inc., Medimmune, Medday, Novartis, Roche, Scifluor, Somahlution, Teva pharmaceuticals, TG Therapeutics, and UT Houston. Dr. Cutter is employed by the University of Alabama at Birmingham and is president of Pythagoras, Inc., a private consulting company located in Birmingham, AL, USA.
J. Hobart has received consulting fees, honoraria and support to attend meetings or research support from Acorda, Asubio, Bayer Schering, Biogen Idec, F. Hoffmann-La Roche Ltd, Genzyme, Merck Serono, Novartis, Oxford PharmaGenesis, Oxford Health Policy Forum and Teva.
J. Kuhle has received speaker fees, research support, travel support and/or served on advisory boards for ECTRIMS, Swiss MS Society, Swiss National Research Foundation (320030_160221), University of Basel, Bayer, Biogen, F. Hoffmann-La Roche Ltd, Genzyme, Merck, Novartis, Protagen AG and Teva.
J. Oh has received research grant funding from the MS Society of Canada, National MS Society, Brain Canada, Biogen-Idec, and Sanofi-Genzyme; and has received personal compensation for consulting or speaking from EMD-Serono, Sanofi-Genzyme, Biogen-Idec, Novartis, and Roche.
C. Tur acknowledges 2015 postdoctoral research ECTRIMS Fellowships, and has also received honoraria and support from Biogen, Bayer, F. Hoffmann-La Roche Ltd, Ismar Healthcare, Merck Serono, Novartis, Sanofi and Teva.
M. Garas is an employee and shareholder of F. Hoffmann-La Roche Ltd.
F. Model is an employee and shareholder of F. Hoffmann-La Roche Ltd.
M. Manfrini is an employee and shareholder of F. Hoffmann-La Roche Ltd.
J. Wolinsky has served on advisory boards, data monitoring or steering committees and has consulting agreements from the following entities: AbbVie, Actelion, Alkermes, Bayer HealthCare, Biogen, Bionest, Celgene, Clene Nanomedicine, EMD Serono, Forward Pharma A/S, GeNeuro, MedDay Pharmaceuticals, Novartis Pharmaceuticals, Otsuka, PTC Therapeutics, Roche Genentech, Sanofi Genzyme, Strategic Consultants International, Takeda and Teva Pharmaceuticals; royalties are received for outlicensed monoclonal antibodies through UTHealth from Millipore Corporation.